Effects of Glucose Feeding, Cortisol, and Insulin on Liver Glycogen Synthesis in the Rat

Abstract

To determine maximal rates of liver glycogen synthesis in vivo, normal, diabetic and adrenalectomized rats were fasted 48 hr, then were given repeated, heavy oral doses of glucose during a 16-hr period, then fasted 24–32 hr. Liver glycogen was assayed at regular intervals throughout these periods of glucose foeding and subsequent fasting. Normal rats synthesized liver glycogen at an extremely rapid rate of about 1% of fresh liver weight/hr to reach a peak of 16–18 % in 16 hr. Similar rates were observed in similarly fed 3-day cortisol-treated rats. Adrenalectomized rats displayed initially a slow rate of liver glycogen synthesis, but after a 2-hr lag period synthesized liver glycogen almost as rapidly as normal rats. However, the level “plateaued” at about 8–9 % after 8–10 hr. Similarly fed adrenalectomized rats treated with cortisol for 3 days responded exactly like normal rats. Similarly fed alloxan-diabetic rats, whose liver glycogen was depleted by prior glucagon injection, synthesized glycogen initially almost as rapidly as normal rats, but the level “platenued” at about 4–5% in about 4 hr. However, alloxandiabetic rats given insulin at the start of glucose feeding synthesized liver glycogen at rates and with peak levels comparable with those or normal rats. When smaller doses of glucose were fed to normal rats the rate of liver glycogen synthesis was greatly decreased, but under these conditions prior cortisol treatment more than doubled liver glycogen synthesis. The results indicate that cortisol enhances the rate of hepatic glycogenesis when there is inadequate glucose to maintain an optimal rate, and that both insulin and cortisol are required for maximal glycogen storage capacity. Initial rates of liver glycogen depletion on subsequent fasting were not markedly different under the various conditions, but the final levels reached after fasts of approximately 24 hr were characteristic for each condition studied; namely, 0.5–1.0% for normal, 4–5% for cortisol-treated, ∼0 for adrenalectomized, and 1–3% for alloxandiabetic rats. These results also point to a role of cortisol and insulin on the glycogen storage mechanism, and discount any direct, rate-controlling effects of these hormones on glycogen breakdown. Although the high dependence of liver glycogen synthesis on the level of glucose administration is compatible with a rate-determining role of hepatic glucokinase, its activity is too low in fasted and diabetic rats to account for the rate of glycogen synthesis under these conditions. Either the assay of this enzyme does not give its true activity in vivo or other mechanisms of glucose phosphorylation exist. Another enzymatic activity which meets the requirements for an auxiliary mechanism of glucose phosphorylation is the glucose:inorganic pyrophosphate phosphotransferase activity of glucose-6-phosphatase, as revealed recently by Nordlie and others. (Endocrinology81: 486, 1967)